Process and means for the eradication of fleas in the habitats of small mammals

ABSTRACT

Method for eradicating fleas in domestic or accommodation premises of a domestic or laboratory mammal is provided. The method involves topically applying, at least monthly, to the domestic or laboratory mammal, a parasitically effective amount of compound of Formula I.

RELATED APPLICATIONS

This application was filed pursuant to 35 U.S.C. § 371 frominternational application PCT/FR98/00601, filed on Mar. 25, 1998, which,in turn, claims priority from French Application 97/03709, filed on Mar.26, 1997.

The present invention relates to a procedure for the eradication ofparasites, namely parasites of the order of Siphonaptera, especiallyfleas, such as, for example, Ctenocephalides felis and canis, butlike-wise the other fleas of small mammals such as, for example, rabbitsor laboratory animals.

The control of parasites of small domestic mammals, for example dogs andcats, and especially of fleas, is known to be extremely difficult.

Generally, it is attempted to control the animals themselves, eitherwith the aid of flea collars containing various insecticides, or bytopical application of preparations based on insecticides.

Nevertheless, the fleas always remain present in the environment of theanimal, and especially in the premises of pets, such as domesticpremises, kennels or catteries, as well as laboratories keeping animals.

The eradication of fleas in these premises with the aid of pesticides oragents for chemical treatment or the premises is a difficult operationand, except for permanently leaving the premises covered in aninsecticidal substance, which can, in the long term, have an undoubtedtoxicity, reinfestation takes place rapidly.

Thus it only remains to regularly treat the animals with the aid ofinsecticides having a period of efficacy which is as great as possible,in order to reduce the periodicity and the cost of the treatments.

Thus the use has recently been proposed, for the treatment of fleas andof ticks in small animals, of topical preparations in the form ofpreparations for spraying or of concentrated preparations for pointcutaneous application (spot on) whose active principle is formed by1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole, whosenon-proprietary name is fipronil.

In fact, the compounds belonging to the pyrazole, especiallyphenylpyrazole, families described in the Patents EP-A-295 217 andEP-A-352 944 have turned out to be extremely efficacious against fleas.

The period of anti-flea efficacy of fipronil, in the form of aconcentrated solution for point application, called a spot on solution,can exceed 2 to 3 months in dogs and six weeks in cats.

In view of these performances, the users are naturally tempted toprolong the periods between two applications so as to benefit from thiseffect of long duration.

A possible explanation for the long duration of activity on the animalcan be connected to the observation that fipronil dissolves in the sebumand the sweat glands to be released over a long time.

In a communication (Meo N.J. et al.; Proc. Am. Assoc. Vet. Parasitol (41Meet., 52, 1996)), it was stated that there was a considerable increasein the percentage of non-reappearance of fleas in non-treated premisesif the animals frequenting these premises (cats, dogs) received monthlyadministrations of sprays of the product Frontline® Spray containingfipronil.

The present invention proposes to simplify and to further improve thisflea control.

A subject of the invention is thus a procedure for eradication of fleasin domestic or accommodation premises of mammals of small size,especially cats and dogs, characterized in that a concentrated topicalpreparation for point application, of the spot-on type in anefficaciously parasiticidal quantity of a compound of formula I or,optionally, of formula II is applied periodically to the animal or theanimals of the premises considered, according to a monthly periodicity.

The formula I is the following formula:

in which:

R₁ is CN or methyl or a halogen atom;

R₂ is S(O)_(n)R₃ or 4,5-dicyanoimidazol-2-yl or haloalkyl;

R₃ is alkyl or haloalkyl;

R₄ is a hydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇, C(O)—R₇,C(O)O—R₇, alkyl, haloalkyl or OR₈ radical or an —N═C(R₉) (R₁₀) radical;

R₅ and R₆ independently are the hydrogen atom or an alkyl, haloalkyl,C(O)alkyl, alkoxycarbonyl or S(O)_(r)CF₃ radical; or R₅ and R₆ cantogether form a divalent alkylene radical which can be interrupted byone or two divalent heteroatoms, such as oxygen or sulphur;

R₇ is an alkyl or haloalkyl radical;

R₈ is an alkyl or haloalkyl radical or a hydrogen atom;

R₉ is an alkyl radical or a hydrogen atom;

R₁₀ is a phenyl or heteroalkyl group which is optionally substituted byone or more halogen atoms or groups such as OH, —O-alkyl, —S-alkyl,cyano or alkyl;

R₁₁ and R₁₂ are, independently of one another, a hydrogen or halogenatom, or optionally CN or NO₂;

R₁₃ is a halogen atom or a haloalkyl, haloalkoxy, S(O)_(q)CF₃ or SF₅group;

m, n, q and r are, independently of one another, an integer equal to 0,1 or 2;

X is a trivalent nitrogen atom or a C—R₁₂ radical, the three othervalencies of the carbon atom being part of the aromatic ring;

with the reservation that when R₁ is methyl, R₃ is haloalkyl, R₄ is NH₂,R₁₁ is Cl, R₁₃ is CF₃ and X is N; or when R₂ is4,8-dicyanoimidazol-2-yl, R₄ is Cl, R₁₁ is Cl, R₁₃ is CF₃ and X is═C—Cl.

The formula II is the following formula:

where Y is hydrogen or halogen

R₁₄ is hydrogen or methyl

and Z is —(CH₂)_(n)— with n=1 or 2.

Preferably, in the formula (I),

R₁ is CN or methyl;

R₂ is S(O)_(n)R₃;

R₃ is haloalkyl or ethyl

R₄ is a hydrogen or halogen atom; or an NR₅R₆, S(O)_(m)R₇, C(O)R₇,alkyl, haloalkyl or OR₈ radical or an —N═C(R₉) (R₁₀) radical;

R₅ and R₆ independently are the hydrogen atom or an alkyl, haloalkyl,C(O)alkyl, S(O)_(r)CF₃ radical; or R₅ and R₆ can together form adivalent alkylene radical which can be interrupted by one or twodivalent heteroatoms, such as oxygen or sulphur;

R₁₁ and R₁₂ are, independently of one another, a hydrogen or halogenatom;

with the reservation that when R₁ is methyl, R₃ is haloalkyl, R₁ is NH₂,R₁₁ is Cl, R₁₃ is CF₃ and X is N.

Compounds of formula (I) which will be considered are very particularlythose in which R₁ is CN. Compounds will also be considered in which R₁₃is haloalkyl, preferably CF₃, or R₂ is S(O)_(n)R₃ with R₃ beinghaloalkyl or X=C—R₁₂, R₁₂ being a halogen atom. It is also preferredthat R₁₁ is a halogen atom.

A preferred class of compounds of formula (I) is formed by the compoundswhere R₁ is CN, R₃ is haloalkyl, R₄ is NH₂, R₁₁ and R₁₂ areindependently of one another a halogen atom, and/or R₁₃ is haloalkyl.

The alkyl radicals of the definition of the compounds of formulae (I)generally comprise from 1 to 6 carbon atoms. The ring formed by thedivalent alkylene radical representing R₅ and R₆ as well as the nitrogenatom to which R₅ and R₆ are attached is generally a ring with 5, 6 or 7members.

A compound of formula (I) which is very particularly preferred in theinvention is

1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole, called fipronilbelow.

Among numerous other advantageous compounds, it is possible to mention1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—C₂H₅]-5-NH₂-pyrazole.

The compounds of formula (I) can be prepared according to one or otherof the processes described in the Patent Applications WO-A-87/3781,93/6089, 94/21606 or European EP-A-0 295 117, or any other proceduredependent on the competence of the specialist in chemical synthesis. Forthe chemical preparation of the products of the invention, the personskilled in the art is considered as having at his disposition, amongother things, all the contents of “Chemical Abstracts” and documentswhich are cited there.

Preferably, in the compound of formula (II) Y=Cl, R₁₄=H and n=1, that isto say

1-[(6-chloro-3-pyridinyl)methyl]-4,5-dihydro-N-nitro-1H-imidazol-2-amineor imidaclopride.

The compounds of the formula (II) can be prepared by the correspondingprocedures described, for example, in EP-A-0 192 060.

Monthly periodicity is ideally understood as meaning one treatment everymonth but it is understood that the invention can be practised at ahigher rate, for example twice weekly or every three weeks, oroptionally, but in a non-preferred fashion, a slightly lower rate, forexample every five weeks.

The preferred periodicity is the monthly periodicity, a higher rateresulting in a needless consumption. In addition, the monthly rate hasthe advantage of allowing the user to memorize and to plan theapplications.

When the premises contain several animals, it is preferable, and moresimple, to treat all the animals at the same time.

The efficaciously parasiticidal quantity, in the sense of the invention,is the quantity used to eradicate fleas on the animal itself and maythus correspond to doses already recommended for the topical treatmentof the animal for the formulations already used commercially. Such adose must be able to protect the animal itself for a period of at leastone month.

The dose of active compound is, preferably, between 0.3 and 60 mg, andpreferably between 5 and 15 mg per kilo of body weight per treatedanimal.

The treatment according to the invention can be carried outcontinuously, optionally taking account of the infestation seasons whereinfestation is seasonal. Such a continuous treatment is preferred forthe premises where numerous animal entries occur, for example farms,kennels, catteries or veterinary clinics.

In a particularly preferred manner, concentrated preparations for pointapplication of “spot on” type, formulae for which the preparation volumeapplied to the animal is of the order of 0.3 to 1 ml, preferably 0.5 mlfor cats, and of the order of 0.3 to 3 ml for dogs, as a function of theweight of the animal will be preferred.

This preparation can contain, apart from the active principle itself, acrystallization inhibitor, an organic solvent and an organic cosolvent.

Preferably, the active compound, especially the compound of formula I,can be present in the formulation at the rate of a concentration of 1 to20% and preferably of 5 to 15% (percentage in weight by volume).

The object of the procedure according to the invention can benon-therapeutic, involving on the one hand cleaning the hair and theskin of the animals by eliminating the parasites present and by avoidingtheir waste and excrement so that the animal has a coat which ispleasant to the eye and to the touch, likewise consisting of suppressingthe appearance and the development of fleas in the premises inhabited bythe animal.

The object can also be therapeutic when it consists in treating aparasitosis having pathogenic consequences.

The concentrated compositions for point application can advantageouslycomprise:

a) the compound of formula I

b) a crystallization inhibitor, especially present at a rate of 1 to 20%(W/V), preferably of 5 to 15%, this inhibitor responding to the testaccording to which:

0.3 ml of a solution comprising 10% (W/V) of the compound of formula (I)in the solvent defined under c) below, as well as 10% of this inhibitor,are placed on a glass slide at 20° C. for 24 hours, following which fewor no crystals, especially less than 10 crystals, preferably 0 crystals,are observed with the naked eye on the glass slide,

c) an organic solvent having a dielectric constant of between 10 and 35,preferably between 20 and 30, the content of this solvent c) in thetotal composition preferably representing the remainder to 100% of thecomposition,

d) an organic cosolvent having a boiling point lower than 100° C.,preferably lower than 80° C., and having a dielectric constant ofbetween 10 and 40, preferably between 20 and 30; this cosolvent canadvantageously be present in the composition according to aweight/weight (W/W) ratio of d)/c) of between {fraction (1/15)} and ½.The solvent is volatile in order to serve especially to promote dryingand is miscible with water and/or with the solvent c).

Although this is not preferred, the composition for point applicationcan optionally comprise water, especially at a rate of 0 to 30% (volumeper volume V/V), in particular of 0 to 5%.

The composition for point application can also comprise an antioxidantagent intended to inhibit oxidation in the air, this agent especiallybeing present at a rate of 0.005 to 1% (W/V), preferably of 0.01 to0.05%.

The compositions according to the invention intended for pets,especially dogs and cats, are applied by spotting on; this generallyconsists of a localized application on a surface zone of less than 10cm², especially of between 5 and 10 cm², in particular at two points andpreferably localized between the shoulders of the animal. Afterdeposition, the composition diffuses, especially over all the body ofthe animal, then dries without crystallizing, nor modifying theappearance especially absence of any whitish deposit or dustyappearance) nor affecting the coat.

The compositions for point application according to the invention areparticularly advantageous by virtue of their efficacy, their rapidity ofaction, as well as by virtue of the pleasant appearance of the hair ofthe animals after application and drying.

As organic solvent c) which can be used in the invention, it is possibleto mention in particular: acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycoln-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethylether, ethylene glycol monomethyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone, especially N-methyl-pyrrolidone,diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate,or a mixture of at least two of these.

As crystallization inhibitor b) which can be used in the invention, itis possible to mention in particular:

polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol, polyethoxylated sorbitan esters; lecithin,carboxymethylcellulose sodium, acrylic derivatives such as methacrylatesand others,

anionic surfactants such as alkali metal stearates, especially ofsodium, of potassium or of ammonium; calcium stearate; triethanolaminestearate; sodium abietate; alkylsulphates, especially sodiumlaurylsulphate and sodium cetylsulphate; sodiumdodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids,especially those derived from copra oil,

cationic surfactants such as water-soluble quaternary ammonium salts offormula N⁺R′R″R′″R″″, Y⁻ in which the R radicals are optionallyhydroxylated hydrocarbon radicals, and Y⁻ is an anion of a strong acid,such as halide, sulphate and sulphonate anions; cetyltrimethylammoniumbromide is among the cationic surfactants utilizable,

the amine salts of formula N⁺R′R″R′″ in which the R radicals areoptionally hydroxylated hydrocarbon radicals; octadecylaminehydrochloride is among the cationic surfactants utilizable,

the non-ionic surfactants such as optionally polyethoxylated sorbitanesters, in particular Polysorbate 80, polyethoxylated alkyl ethers;polyethylene glycol stearate, polyethoxylated castor oil derivatives,polyglycerol esters, polyethoxylated fatty alcohols, polyethoxylatedfatty acids, copolymers of ethylene oxide and propylene oxide,

amphoteric surfactants such as substituted lauryl betaine compounds, orpreferably a mixture of at least two of these.

Particularly preferably, a crystallization inhibitor pair will be used,namely the combination of a surface-active agent. These agents willespecially be chosen from the compounds mentioned as crystallizationinhibitor b).

Among the filmogenic agents of particularly interesting polymeric type,it is possible to mention:

different grades of polyvinylpyrrolidone,

polyvinyl alcohols, and

copolymers of vinyl acetate and vinylpyrrolidone.

As far as surface-active agents are concerned, very particular mentionwill be made of non-ionic surfactants, preferably polyethoxylated estersof sorbitan and especially the different grades of Polysorbates, forexample Polysorbate 80.

The filmogenic agent and surface-active agent will especially be able tobe incorporated in close or identical quantities in the limit of totalquantities of crystallization inhibitor otherwise mentioned.

The pair thus formed remarkably ensures the objectives of absence ofcrystallization on the hair and of maintenance of the cosmeticappearance of the coat, that is to say without tendency to sticking orto sticky appearance, despite the high concentration of active material.

As cosolvent d), it is possible to mention in particular: absoluteethanol, isopropanol, methanol.

As antioxidant agent, conventional agents are especially used, such as:butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate, or a mixture of atleast two of these.

The compositions for point application according to the invention areusually prepared by simple mixing of the constituents as defined above;advantageously, a start is made by mixing the active material in theprincipal solvent, and the other ingredients or adjuvants are thenadded.

In an advantageous manner, it is possible to provide for ready-for-usecompositions, prepared for animals of 1-10, 10-20, 20-40 kgrespectively.

In a particularly preferred manner, the composition according to theinvention can be present in the form of a concentrated emulsion orsolution suspension for point application on a small cutaneous zone ofthe animal, generally between the two shoulders (spot-on type solution).

The procedure according to the invention can likewise comprise, inaddition, the administration of another parasiticide, preferably at thesame rate, and preferably administered concomitantly, and preferentiallywith the aid of a single composition comprising a mixture or acombination of this parasiticide and of an insecticide of formula I orII. These combined parasiticides are not known in themselves to have anactivity allowing them to act directly on the insects in the stagethereof removed from the animal, but they can be useful for furtherincreasing the efficacy against fleas resident on the animal andlikewise for reducing the possible risks of insecticide resistanceoccurring.

Among these combined parasiticides it is possible especially to mentionthe compounds mimicking juvenile hormones, especially:

azadirachtin—Agridyne

diofenolan (Ciba Geigy)

fenoxycarb (Ciba Geigy)

hydroprene (Sandoz)

kinoprene (Sandoz)

methoprene (Sandoz)

pyriproxyfene (Sumitomo/Mgk)

tetrahydroazadirachtin (Agridyne)

and4-chloro-2-(2-chloro-2-methylpropyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-oneand chitin synthesis inhibitors, especially:

chlorfluazuron (Ishihara Sangyo)

cyromazine (Ciba Geigy)

diflubenzuron (Solvay Duphar)

fluazuron (Ciba Geigy)

flucycloxuron (Solvay Duphar)

flufenoxuron (Cyanamid)

hexaflumuron (Dow Elanco)

lufenuron (Ciba Geigy)

novaluron (Isagro, Italy)

tebufenozide (Rohm & Haas)

teflubenzuron (Cyanamid)

triflumuron (Bayer)

these compounds being defined by their international non-proprietaryname (The Pesticide Manual, 10th edition, 1994, Ed. Clive Tomlin, GreatBritain).

It is possible to mention, likewise as chitin synthesis inhibitors,compounds such as1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

The preferred combined compounds are methoprenes, pyriproxyphenes,hydroprene, cyromazine, lufenuron, novaluron and1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea.

It is preferred that the administration of the two types of compounds isconcomitant and preferably simultaneous.

Preferably, the treatment is conducted so as to administer to the animala dose of 0.1 to 40, and especially of 1 to 20, mg/kg for the derivativeof formula I or II and a dose of 0.1 to 40, especially 1 to 30, mg/kgfor the combined compound.

The preferred doses are from 5 to 15 mg/kg for the compound of formula Iand from 0.5 to 15 mg/kg for the combined compounds.

The proportions by weight of the compound of formula I or II and of thecombined compound are, preferably, between 80/20 and 20/80.

In another form of preparation, the combined parasiticide can be anendectocidal parasiticide of macrocyclic lactone type.

Preferably, this parasiticide is chosen from the group formed by theavermectins, ivermectin, abamectin, doramectin, moxydectin, themilbemycins and the derivatives of these compounds.

The structure, the characteristics and the processes of production ofthese compounds are well known to the person skilled in the art and itwill be possible to refer to the widely available technical andcommercial literature. For the avermectins, ivermectin and abamectin, itis possible to refer, for example, to the work “Ivermectin andAbamectin”, 1989 by M. H. FISCHER and H. MROZIK, William C. CAMPBELL,ed. Springer Verlag or ALBERT-SCH™NBERG et al. (1981) “AvermectinStructure Determination”. J. Am. Chem. Soc. 103: 4216-4221. Fordoramectin, it will be possible to consult, especially, “VeterinaryParasitology” vol. 49 No. 1, July 1993: 5-15. For the milbemycins itwill be possible to refer, inter alia, to DAVIES H. G. et al., 1986,“Avermectins and Milbemycins”. Nat. Prod. Rep. 3: 87-121, Mrozik H. etal., 1983, Synthesis of milbemycins from avermectins, Tetrahedron lett.24: 5333-5336 as well as U.S. Pat. No. 4,134,973.

The administration of the two types of compounds can be concomitant andpreferably simultaneous in the form of a single composition.

The efficacious quantity of endectocidal compound is preferably frombetween 0.1 μg, preferentially 1 μg, and 1 mg, and in a particularlypreferred manner 5 to 200 μg/kg of animal weight. The proportions byweight between the compound of formula (I) or (II) and the endectocidalcompound are preferably between 5/1 and 10,000/1.

The mechanisms by which the fleas disappear from the premises themselvesare not well known and the efficacy of the invention is particularlysurprising.

An object of the present invention is likewise packed outfits or kitscomprising one or more units of compositions which can be used in theinvention representing a plurality of monthly doses intended to besuccessively administered to an animal for carrying out the procedurefor a long period, for example, according to the country, for a periodof one year or for a period of one season of flea infestation.

Preferably, this kit contains a plurality of different monthly unitdoses, for example 3 or 6 (for one season) or 12 (for one year)different doses contained in as many containers of spot on or pour ontype. In this form of implementation, several kit versions are providedas a function of the weight of the animals.

The kit likewise comprises means of explanation such as a note forensuring the periodicity of the use of the doses.

In another form of implementation, the different doses can be containedin a single container equipped with means for ensuring the applicationof a dose corresponding to the quantity intended to be administeredmonthly. This means can be, for example, a metering pump or valveensuring the delivery of a precise dose. It can also, more simply, beformed of a graduation with regard to a transparent container surface,allowing the liquid volume of composition which remains in the containerto be known.

An object of the invention is likewise the use of a compound of formulaI or of formula II for the preparation of a composition for theeradication of fleas in domestic or accommodation premises of mammals ofsmall size, especially cats and dogs, by periodic application to theanimal or the animals of the premises considered of a topicalpreparation as defined hereinabove in an efficaciously parasiticidalquantity of a compound of formula I, or optionally of formula II,according to a monthly periodicity.

Other advantages and characteristics of the invention will becomeapparent from reading the following description, by way of non-limitingexample.

EXAMPLE 1

The test used dogs in good health.

The dogs were divided by groups of three dogs into enclosures of areaapproximately 4.80 m long (16 feet) and 1.5 m wide (5 feet) eachcontaining a shelter and soil especially favourable to the developmentof the immature stages of the fleas (Ctenocephalides felis). All thedogs were voluntarily and identically preinfested and then regularlyinfested by fleas at a rate such that the total number of fleas carriedby each animal of the control group A did not fall significantly below20.

A total of 18 dogs, that is to say six enclosures, was allocated to thecontrol group A.

A group C of six dogs (2 enclosures) preinfested in this way receivedthe treatment according to the invention by application of a cutaneouspoint solution having a concentration of 10% of fipronil.

The doses of concentrated composition for local cutaneous application offipronil were as follows:

Weight of the animal Doses  5-10 kg 0.67 ml 10-20 kg 1.34 ml 20-40 kg2.68 ml

The animals of group C were treated on day 0 and then every 28 days,that is to say the days 28, 56 and 84.

The checks (weekly counting of the eggs, counting on the body in weeks1, 3, 5, 7, 9 and counting on the comb in weeks 2, 4, 6, 8, 10, 11, 12)showed a rate of control of the infestation equal to 100%.

A similar test on cats gave the same results, that is to say a totalabsence of reinfestation.

What is claimed is:
 1. A method for the eradication of fleas in domesticor accommodation premises of a domestic or laboratory mammal, comprisingtopically applying, at least monthly, to a localized region having asurface area of 10 cm² or less on the domestic or laboratory mammal, aparasitically effective amount of a spot-on topical preparationcomprising a veterinarily acceptable vehicle and a compound of FormulaI:

in which: R₁ is CN; R₂ is S(O)_(n)R₃; R₃ is haloalkyl; R₄ is NH₂; R₁₁and R₁₂ are, independently of one another a halogen atom; R₁₃ is ahaloalkyl; n is an integer equal to 0, 1 or 2; X is a C—R₁₂ radical;wherein, when the preparation is so applied to the mammal, through theaction of the compound and the vehicle, the compound diffuses over themammal's body, and then dries without crystallization and withoutmodifying the mammal's appearance and coat, and wherein said mammal isselected from the group consisting of canine and feline.
 2. The methodaccording to claim 1, wherein R₁₃ is CF₃.
 3. The method according toclaim 1, wherein the compound of Formula (I) is1-[2,6-Cl₂-4-CF₃-phenyl]-3-CN-4-[SO—CF₃]-5-NH₂-pyrazole.
 4. The methodaccording to claim 1, wherein the dose of the compound is between 0.3and 60 mg/kg of treated mammal
 5. The method according to claim 1,wherein the dose of the compound is between 5 and 15 mg/kg of treatedanimal.
 6. The method according to claim 1, wherein the amount of thetopical preparation applied to felines is about 0.3 to 1 ml/kg.
 7. Themethod according to claim 6, wherein the amount of the topicalpreparation applied to felines is about 0.3 to 0.5 ml/kg.
 8. The methodaccording to claim 1, wherein the amount of the topical preparationapplied to canines is about 0.3 to 3 ml/kg.
 9. The method according toclaim 1, wherein the topical preparation further comprises acrystallization inhibitor, an organic solvent and an organic co-solvent.10. The method according to claim 1, wherein when the premises containseveral mammals, all the mammals are treated at the same time.
 11. Themethod according to claim 1, wherein the treatment is carried outcontinuously, optionally taking account of the infestation seasons whereinfestation is seasonal.